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The Energy Status of Astrocytes Is the Achilles' Heel of Eif2b

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The Energy Status of Astrocytes Is the Achilles' Heel of Eif2b cells Article The Energy Status of Astrocytes Is the Achilles’ Heel of eIF2B-Leukodystrophy Melisa Herrero 1, Maron Daw 1, Andrea Atzmon 1 and Orna Elroy-Stein 1,2,* 1 Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel; [email protected] (M.H.); [email protected] (M.D.); [email protected] (A.A.) 2 Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel * Correspondence: [email protected] Abstract: Translation initiation factor 2B (eIF2B) is a master regulator of global protein synthesis in all cell types. The mild genetic Eif2b5(R132H) mutation causes a slight reduction in eIF2B enzymatic activity which leads to abnormal composition of mitochondrial electron transfer chain complexes and impaired oxidative phosphorylation. Previous work using primary fibroblasts isolated from Eif2b5(R132H/R132H) mice revealed that owing to increased mitochondrial biogenesis they exhibit normal cellular ATP level. In contrast to fibroblasts, here we show that primary astrocytes isolated from Eif2b5(R132H/R132H) mice are unable to compensate for their metabolic impairment and exhibit chronic state of low ATP level regardless of extensive adaptation efforts. Mutant astrocytes are hypersensitive to oxidative stress and to further energy stress. Moreover, they show migration deficit upon exposure to glucose starvation. The mutation in Eif2b5 prompts reactive oxygen species (ROS)-mediated inferior ability to stimulate the AMP-activated protein kinase (AMPK) axis, due to a requirement to increase the mammalian target of rapamycin complex-1 (mTORC1) Citation: Herrero, M.; Daw, M.; signalling in order to enable oxidative glycolysis and generation of specific subclass of ROS-regulating Atzmon, A.; Elroy-Stein, O. The proteins, similar to cancer cells. The data disclose the robust impact of eIF2B on metabolic and redox Energy Status of Astrocytes Is the homeostasis programs in astrocytes and point at their hyper-sensitivity to mutated eIF2B. Thereby, Achilles’ Heel of it illuminates the central involvement of astrocytes in Vanishing White Matter Disease (VWMD), a eIF2B-Leukodystrophy. Cells 2021, 10, genetic neurodegenerative leukodystrophy caused by homozygous hypomorphic mutations in genes 1858. https://doi.org/10.3390/ encoding any of the 5 subunits of eIF2B. cells10081858 Keywords: astrocytes; eIF2B-leukodystrophy; translation regulation; impaired mitochondria func- Academic Editor: Ann Saada tion; energy stress; oxidative stress; ROS; AMPK; mTOR Received: 22 April 2021 Accepted: 19 July 2021 Published: 22 July 2021 1. Introduction Publisher’s Note: MDPI stays neutral Translation initiation factor 2B (eIF2B), a master regulator of protein synthesis under with regard to jurisdictional claims in normal and stress conditions, is a decameric complex composed of two homo-pentamers of published maps and institutional affil- eIF2B1-5 subunits which are evolutionary conserved from yeast to mammals [1,2]. While iations. knock-out of EIF2B is lethal, hypo-active eIF2B due to hypo-morphic mutations specifically affect the phenotype of brain glial cells, although eIF2B is essential for every cell type. The most compelling evidence for the latter statement is the neurodegenerative pathology termed Vanishing White Matter Disease (VWMD) or eIF2B-leukodystrophy, caused by two mutated alleles of any of the 5 genes encoding eIF2B subunits (OMIM 306896) [3]. More Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. than 160 different mutations associated with variable effects on eIF2B stability/enzymatic This article is an open access article activity, lead to progressive deterioration of brain white matter, neurological symptoms distributed under the terms and and early death [4,5]. eIF2B serves as the guanine exchange factor of the translation conditions of the Creative Commons initiation factor eIF2. At each round of translation initiation step, active GTP-bound eIF2 Met Attribution (CC BY) license (https:// binds to methionine-charged initiator tRNAi followed by association of the eIF2-GTP- Met creativecommons.org/licenses/by/ Met-tRNAi complex with 40S ribosomal subunit. Upon successful AUG recognition, 4.0/). eIF2-GDP is released and recycled back to eIF2-GTP by eIF2B [6,7]. The enzymatic activity Cells 2021, 10, 1858. https://doi.org/10.3390/cells10081858 https://www.mdpi.com/journal/cells Cells 2021, 10, 1858 2 of 23 of eIF2B is tightly regulated by multiple signals in response to physiological cues within the cell. For example, eIF2B is inhibited via phosphorylation by glycogen synthase kinase 3 (GSK3) [8]. Another important inhibitory mechanism under various stress conditions is mediated by phosphorylation of the alpha subunit of eIF2 by one of four different kinases (heme-regulated inhibitor, HRI; general control non-derepressible-2, GCN2; protein kinase R, PKR; and PKR-like endoplasmic reticulum kinase, PERK) which turns it into a competitive inhibitor of eIF2B. The latter marks the beginning of an expression program termed integrated stress response (ISR) which also includes feedback dephosphorylation of eIF2α [9]. For the study of VWMD, we previously generated a mouse strain homozygous for R132H mutation in Eif2b5, the gene encoding the catalytic subunit [10]. Our previous studies using wild-type (WT) and Eif2b5R132H/R132H (Mut) mice include generation of transcriptome and proteome datasets from embryo fibroblasts and whole brains. These studies indicated that ~20% decrease in brain eIF2B enzymatic activity is responsible for a mixture of up- and down-regulation of numerous genes at the mRNA and/or protein lev- els [11–13]. Obviously, the omics datasets represent the anomalous homeostasis state of the mutants. Using unbiased omics-related experiments, we revealed the connection between hypo-active eIF2B and mitochondrial impairment. Specifically, an abnormal composition of electron transfer chain (ETC) complexes was discovered [12], followed by consequent biochemical analyses showing impaired oxidative phosphorylation (OXPHOS) and ATP production in primary cultures of embryo fibroblasts, oligodendrocytes precursor cells, and primary astrocytes [13,14]. Moreover, we showed that while Mut fibroblasts fully com- pensate for their faulty OXPHOS by increasing their mitochondria biogenesis, astrocytes and oligodendrocytes fail to achieve complete restoration of mitochondrial respiration per cell, despite their massive adaptation efforts which include substantial mitochondria biogenesis and increased glycolysis rates. The difference in energy requirements between fibroblasts and glial cells could explain in part the asymptomatic phenotype of fibroblasts and the high vulnerability and pathological manifestations of brain glial cells in VWMD patients [13–16].The significant roles of astrocytes, the most abundant glial cells in the brain, in all aspects of brain homeostasis including energy metabolism, prompted us to learn more about their Achilles’ heel given their excessive sensitivity to Eif2b mutations. We focused on mTORC1 and AMPK which are key antagonizing regulators of cellular energy and biomass production [17]. The mTORC1 axis stimulates anabolic pathways and ATP consumption by facilitating protein synthesis, lipogenesis, cell growth, and proliferation [17,18]. AMPK responds to energy stress by inhibiting mTOR and by enhancing catabolic pathways to stimulate ATP production mostly by promoting mitochondrial biogenesis and function and by facilitating fatty acid oxidation (FAO) [19–23]. In the current study, we analyzed primary astrocytes isolated from brains of Mut and WT mice. We discovered that Mut astrocytes suffer from low energy, exhibited by low ATP levels. Despite their poor energetic status, Mut astrocytes show a ROS-mediated inferior ability to stimulate the AMPK axis and favor an adaptation program that includes stimulation of mTORC1 activity, which plays a key role in redox homeostasis and allows oxidative glycolysis, similar to cancer cells. Upon further energy stress imposed by severe limitation of glucose availability, Mut astrocytes exhibit impaired adaptation capacity due to inferior ability to oxidize fatty acids. Consequently, they suffer from compromised ability to execute high ATP-demanding functions such as cell migration. The poor energetic status of Mut astrocytes and their increased vulnerability to ROS and to low glucose availability provides important additional insights to the pathology of VWMD. 2. Materials and Methods 2.1. Mice Wild type (WT; C57BL strain) and Eif2b5R132H/R132H (Mut; mutant) mice were bred and housed in Tel Aviv University animal facility with 14/10 h light/dark cycle in groups of four animals per individually ventilated cage (Lab Products Inc., Seaford, DE, USA) sup- Cells 2021, 10, 1858 3 of 23 plemented with autoclaved wood chips. Animals were fed with irradiated rodent hybrid pellet (#1318M, Altromin; Lage, Germany) and sterile water ad libitum. All experimental procedures were approved by the Tel Aviv University Animal Care Committee according to national guidelines (permit #04-17-022). Breeding and genotyping were performed as previously described [10]. 2.2. Primary Astrocytes Isolation and Usage Brains were extracted from the cranial vault of newborn (P0-P2) WT and Mut mice followed by removal of the midbrain and olfactory bulb. After meninges removal, both hemispheres were dissociated to single-cell suspension by papain digestion using MACS Neural Tissue Dissociation
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